4-hydroxy-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine substitution products



This invention relates to substitution products of 4- hydroxy 5,6,7,S-tetrahydro-pyrido-[4,3-d] pyrimidines, their non-toxic acid addition salts, and to various methods of preparing these compounds.

More particularly, the present invention relates to substitution products of 4-hydroxy-5,6,7,8-tetrahydro-pyrido- [4,3-d1-pyrimidines of the formula wherein R is hydrogen, alkyl, aryl or aralkyl,

R is acyclic hydrocarbon, preferably lower alkyl or lower alkenyl, and

R is hydrogen, alkyl, aralkyl, monoor di-substituted amino, saturated basic heterocycle, such as piperidino, pyrrolidino, morpholino or N'-lower alkyl-piperazino, mercapto, alkyl-mercapto or aralkyhmercapto,

and their non-toxic, pharmacologically acceptable acid addition salts.

The compound of the present invention may be prepared by reacting a piperidone-carboxylic acid lower alkyl ester of the formula RPN -c 0 alkyl wherein R and R have the same meanings as in Formula I, or an acid addition salt thereof with an amidine of the formula HzN wherein R has the same meanings as in Formula I, or with an inorganic or organic acid addition salt of said amidine.

The reaction of the piperidone-carboxylic acid ester II and the amidine III or an acid addition salt thereof is preferably carried out in the presence of an alkaline condensation agent and of an inert solvent at room temperature or at moderately elevated temperatures. Examples of suitable alkaline condensation agents are alkali metal hydroxides, alkali metal carbonates or alkali metal alcoholates. The solvent medium may be water or an organic solvent, such as methanol, ethanol, benzene, tetrahydrofuran, and the like.

In those instances where the above reaction yields compounds of the Formula I wherein R is mercapto or substituted mercapto, the thio substituent in the 2-position may subsequently, if desired, be converted into any of the basic substitutents listed in the definition of R above, namely, by reaction of the 2-thio compound with ammonia, a primary or a secondary amine. This reaction is preferably performed with an excess of the United States Patent 0 3,396,901 Patented Feb. 28, 1967 particular amine and, if necessary, in the presence of an inert organic solvent, such as ethanol, benzene, tetrahydrofuran, and the like. The particular amine in still larger excess may also serve as the solvent medium. The conversion reaction is performed at a temperature between 20 and C. preferably at the boiling point of the solvent medium or the particular amine reactant; in the event that an amine or a solvent with a relatively low boiling point is used, it is recommended to perform the reaction in a closed vessel.

Thus, compounds of the Formula I above wherein R represents a basic substituent, may be prepared either by a one-step or a two-step process.

After isolation from the reaction mixture, the free bases obtained by the above-described processes may, if desired, be converted into their acid addition salts. This is most conveniently accomplished by dissolving the free base in a suitable solvent and then acidifying the solution with the desired acid, preferably a pharmacologically acceptable acid, as defined below. If the free base contairis more than one basic nitrogen atom, acid addition salts with more than one equivalent of the particular acid may be obtained.

The majority of the piperidone-carboxylic acid lower alkyl esters of the Formula II above, which are used as starting materials for the preparation of the novel 5,6,7,8- tetrahydro-pyrido-[4,3-d1-pyrimidine substitution products of the present invention, are well-known compounds. Those which may not be specifically described in the literature, however, may readily be prepared from iminodipropionic acid lower alkyl esters of the formula CH- OH2C O 0 lower alkyl (IV) M.P. of its hydrochloride: 132 C.

(2) N-methyl-5-met hyl piperidone (4) -3-carboxylic acid methyl ester M.P. of its hydrochloride: 129 C.

(3) N-ethyl piperidone (4)-3-carboxylic acid ethyl ester M.P. of its hydrochloride: 143 C.

3 (4) N-(isopropyl)-piperidone-(4)-3 carboxylic acid ethyl ester M.P. of its hydrochloride: 145 C.

(5) N-(n-butyl)-piperidone-(4) 3 carboxylic acid ethyl ester MP. of its hydrochloride: 141 C.

(6) N-isobutyl-piperidone-(4)-3-carboxylic acid ethyl M.P. of its hydrochloride: 125 C.

(7) N methyl 2 (or 6) phenyl-piperidone-(4)-3- carboxylic acid ethyl ester l or CUP) --COOC:H

M.P. of its hydrochloride: 174 C. ture has not yet been established).

A particularly advantageous embodiment of the method of preparing the compounds of the present invention consists of starting with an imino-dipropionic acid lower alkyl ester of the Formula IV, subjecting this compound to the Dieckmann condensation reaction and, without isolating the intermediate product II, reacting the reaction mixture of the Dieckmann reaction with an amidine of the Formula 111, preferably in the presense of water or an inert organic solvent.

The following examples will further illustrate the present invention and will enable others skilled in the art to understand the invention more completely. It should be understood, however, that the invention is not limited to these particular examples.

(The exact struc- Example 1.-Preparati0n 0f 2benzyl-4-hydroxy-6,8-dimethyl-5,6,7,8-retrallydro-pyrido-[4,3-d]-pyrimidine 22.2 gm. of 1,5-dimethyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride, 19.1 gm. of phenylacetamidine hydrochloride and 20.8 gm. of potassium carbonate were each dissolved in 50 cc. portions of water, and the solutions were combined. After briefly heating the solution to 60 C. a crystalline precipitate began to form; the reaction mixture was allowed to stand for a few hours, and the precipitate was then separated by vacuum filtration. The filter cake was recrystallized from methanol, yielding gm. of the compound of the formula having a melting point of 193195 C.

4- Example 2.Preparat '0n of Z-ethylmercapto-4-lzydroxy- 6-metlzyl-5,6,7,8-tetralzydr0-pyrido-[4,3-d]-pyrimidine gm. of methylamino-dipropionic acid-diethyl ester were added to a solution of 11.5 gm. of metallic sodium in 300 cc. of absolute methanol. The methanol was removed by vacuum evaporation, and the residue was heated for one hour at C. in a high vacuum. The sodium enolate of N-methyl-piperidone-(4)-3-carboxylic acid ethyl ester formed thereby was dissolved in 100 cc. of water and a solution of 74 gm. of S-ethyl-isothiourea hydrobromide in 200 cc. of water was added thereto. The reaction mixture was vigorously stirred for three to four hours; thereafter, the precipitate formed during that time was separated by vacuum filtration. The filter cake was washed with cold water and was recrystallized from ethyl acetate. 65 gm. of the compound of the formula Oils-h 1 N 11 were obtained. The product had a melting point of 156-157 C.

Example 3.Preparati0n 0 2 metlzylmercapto 4 hydr0xy-6,8-dimetlzyl 5,6,7,8 tetrahydro-pyrido- [4,3-d]- pyrimidine 30 gm. of 1,5-dimethyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride, 19 gm. of S-methylisothiourea sulfate and 41 gm. of potassium carbonate were each dissolved in separate 40 cc. portions of water while slightly warming, and the individual solutions were combined. The mixture was stirred for five hours, the crystalline precipitate formed during that time was filtered olf, and the filter cake was recrystallized from ethanol. 23 gm. of the compound of the formula wsorn C1I3-N N I OH were obtained. The product had a melting point of 212 C.

Example 4.Preparati0n of 2(di-/z-butyl-am1'n0)-4-/1ydroxy 6,8 dimel/zyl-5,6,7,8-tetrallydro-pyrido-[4,3-d1- pyrimidine A mixture of 11.2 gm. of 2-methylmercapto-4-hydroxy-6,8-dimethyl-5,6,7,8-tetrahydro pyrido [4,3-d1- pyrimidine and 26 gm. of di-n-butylamine was heated for 32 hours at C. in an autoclave made of V A-stain less steel. Thereafter, the unreacted excess dibutylamine was removed by vacuum evaporation, the residue was stirred with a small amount of ethanol, and the crystalline slurry obtained thereby was vacuum filtered.

The filter cake was recrystallized from ethanol, yielding 9 gm. of the compound of the formula I OH having a melting point of 134135 C.

Example 5 .-Preparation of 2-n-hexylamin0-4-lzydr0xy- 6-n-butyl-5,6,7,8-tetrahydr0-pyrid0-[4,3-d] -pyrimidine A mixture of 10 gm. of 2-methylmercapto-4-hydroxy- 6n-butyl-5,6,7,8-tetrahydro-pyrido-[4,3 d] pyrimidine.

and 16 gm. of n-hexylamine was refluxed for twelve hours.

Thereafter, the unreacted excess n-hexylamine was removed by vacuum evaporation, the residue was stirred with a small amount of ether, the crystalline slurry formed thereby was vacuum filtered, and the filter cake was rewere obtained. The product had a melting point of 129 C.

Example 6 Using a procedure analogous to that described in Example 2, 2-methylmercapto-4-hydroxy-6-ethyl-5,6,7,8- tetrahydro-pyrido-[4,3-d] -pyrimidine of the formula having a melting point of 187 C. was prepared from metallic sodium, ethylarnino-dipropionic acid-diethyl ester and S-methyl-isothiourea hydrobromide.

Example 7 Using a procedure analogous to that described in Example 3, 2 methylmercapto 4-hydroXy-6-n-propyl-5,6,7,8- tetrahydro-pyrido-[4,3-d1-pyrimidiue of the formula having a melting point of 198199 C. was prepared from 1-npropyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and S-methyl-isothiourea sulfate.

Example 8 Using a procedure analogous to that described in Example 3, 2-ethylmercapto-4-hydroxy-6-n-propyl-5,6,7,8- tetrahydro-pyrido-[4,3-d] -pyrimidine of the formula having a melting point of 132 C. was prepared from 1-n-propyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and S-ethyl-isothiourea sulfate.

Example 9 Using a procedure analogous to that described in Example 3, 2-ethylmercapto-4-hydroXy-6-isopropyl-5,6,7, S-tetrahydro-pyrido-[4,3-d] -pyrimidine of the formula having a melting point of 153 C. was prepared from l-isopropyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and S-ethyl-isothiourea sulfate.

Example 10 Using a procedure analogous to that described in Example 3, 2-methylmercapto-4-hydroXy-6-n-butyl-5,6,7,

S-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula N SCHs 11-C JEWW I OH having a melting point of 184 C. was prepared from l-n-butyl-piperidone-( r)-3-carboxylic acid methyl ester hydrochloride and S-methyl-isothiourea sulfate.

Example 11 Using a procedure analogous to that described in Example 3, 2-methylmercapto-4-hydroXy-6-isobutyl-5,6,7,8- tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula -SCHa lSO-C-AHPW I OH having a melting point of 207208 C. was prepared from 1-isobuty1-piperidone-(4)-3-carboXylic acid methyl ester hydrochloride and S-methyl-isothiourea sulfate.

Example 12 Using a procedure analogous to that described in EX- ample 1, 2-benzyl-4-hydroxy-6-methyl-5,6,7,8-tetrahydropyrido-[4,3-d]pyrimidine of the formula having a melting point of 2182l9 C. was prepared from l-methyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and phenylacetamidine hydrochloride.

Example 13 Using a procedure analogous to that described in Example l, 2,6,8 trimethyll-hydroxy-5,6,7,S-tetrahydropyrido-[4,3-d]-pyrimidine of the formula having a melting point of l97199 C. was prepared from 1,5-dimethyl-piperidone-(4) -3-carb0xylic acid methyl ester hydrochloride and acetamidine hydrochloride.

Example 14 Using a procedure analogous to that described in EX- ample 1, 2 benzyl-4-hydroxy-6ethyl-5,6,7,8-tetrahydropyrido-[4,3-d] -pyrimidine of the formula Cilia-W I OH having a melting point of 177178 C. was prepared from 1-ethyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and phenylacetamidine hydrochloride.

7 Example 15 Using a vprocedure analogous to that described in EX- ample 1, 2 methyl 4-hydroxy-6-n-propyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 165-167 C. Was prepared from 1-n-propyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and acetamidine hydrochloride.

Example 16 Using a procedure analogous to that described in Example 1, 2 benzyl 4 hydroxy-6-isopropyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula Using a procedure analogous to that described in Example 1, 2-methyl-4-hydroxy-6-n-butyl-5,6,7,8-tetrahydropyrido-[4,3-d]-pyrimidine of the formula having a melting point of 146-147 C. was prepared from l-n-butyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and acetamidine hydrochloride.

Example 18 Using a procedure analogous to that described in Example 1, 2-benzyl-4-hydroxy-6-n-butyl-5,6,7,S-tetrahydropyrido-[4,3-d1-pyrimidine of the formula having a melting point of 113-1 14 C. was prepared from l-n-butyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and phenylacetarnidine hydrochloride. The maleic acid addition salt of the free base had a melting point of 151-153 C.

Example 19 Using a procedure analogous to that described in Example 1, 2 n-butyl-4-hydroxy--n-propyl-5,6,7,8,-tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula having a melting point of 109-111 C. was prepared from l-n-propyl-piperidone-( l)-3-carboxylic acid methyl ester hydrochloride and a amino a imino-pentane hydrochloride.

8 Example 20 Using a procedure analogous to that described in Example 4, Z-(di-n-butyl-amino)-4-hydroxy-6-methyl-5,6,7, 8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I O H having a melting point of 135137 C. was prepared from 2 methylmercapto 4-hydroxy-6-methyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine and di-n-butylamine.

Example 21 Using a procedure analogous to that described in Example 5, 2 piperidino-4-hydroXy-6-methyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula (3113-1. i N OH having a melting point of 231 C. was prepared from 2- rnethylmercapto 4-hydroxy-6-methyl-5,6,7,8,-tetrahydropyrido-[4,3-d1-pyrimidine and piperidine.

Example 22 Using a procedure analogous to that described in Example 5, 2-morpholino-4-hydroxy-6-methyl-5,6,7,8-tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula Cal ll 1.

I o H having a melting point of 222223 C. was prepared from 2-methylmercapto-4-hydroxy 6 methyl-5,6,7,8-tetrahydropyrido-[4,3-d]-pyrimidine and morpholine.

Example 23 Using a procedure analogous to that described in Example l, Z-dimethylamino-4-hydroXy-6,S-dimethyl-S,6,7, S-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of l85l86 C. was prepared from l,S-dimethyl-piperidone (4) 3-carboxylic acid methyl ester hydrochloride and N,N-dimethyl-guanidine hydrochloride.

Example 24 Using a procedure analogous to that described in Example 5, 2-morpholino-4-hydroXy-6,8-dimethyl-5,6,7,8-tetrahydro-pyrido-[4,3-d] -pyrimidine of the formula lW l having a melting point of 197498 C. Was prepared from 2-methylrnercapto-4-hydroxy 6,8 dimethyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine and morpholine.

having a melting point of 9496 C. was prepared from 2- methylmercapto-4-hydroxy 6 ethyl-5,6,7,8-tetrahydropyrido-[4,3-d]-pyrin1idine and di-n-butylamine.

Example 26 Using a procedure analogous to that described in EX- ample 1, 2-dimethylamino-4-hydroXy-6-ethyl-5,6,7,8-tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula having a melting point of 5657 C. was prepared from 1-ethyl-piperidone-(4)-3-carboxylic acid methyl ester hydrochloride and N,N-dimethy1-guanidine hydrochloride.

Example 27 Using a procedure analogous to that described in EX- ample 5, Z-pyrrolidino-4-hydroxy-6-ethy1-5,6,7,S-tetrahydro-pyrido-[4,3-dJ-pyrimidine of the formula I OH having a melting point of 190192 C. was prepared from Z-methylmercapto-4hydroxy 6 ethyl-5,6,7,8-tetrahydropyrido-[4,3-d] -pyrimidine and pyrrolidine.

Example 28 Using a procedure analogous to that described in EX- arnple 5, 2-piperidino-4-hydroxy 6 ethyl-5,6.,7,8-tetrahydro-pyrido-[4,3-d]-pyrirnidine of the formula I OH having a melting point of 170 C. was prepared from 2- methylmercapto-4-hydroxy 6 ethyl-5,6,7,8-tetrahydropyrido-[4,3-d]-pyrimidine and piperidine.

Example 29 Using a procedure analogous to that described in EX- arnple 5, 2'morpholino-4-hydroXy-6ethyl-5,6,7,8-tetrahydro-pyrido-[4,3-dJ-pyrimidine of the formula I OH having a melting point of 186 C. was prepared from 2- methylmercapto-4-hydroxy-6 ethyl S,6,7,8 tetrahydropyrido-[4,3-d]-pyrimidine and morpholine.

Example 30 Using a procedure analogous to that described in Example 5, 2-(N-methyl-piperazino) 4 hydroxy 6 ethyl- 10 5,6,7,S-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula CzHs-N i N I OH having a melting point of 162163 C. was prepared from 2-methylmercapto-4-hydroxy-6-ethy1-5,6,7,8 tetrahydropyrido-[4,3-d]-pyrimidine and N-methyl-piperazine.

Example 31 Using a procedure analogous to that described in Example 5, 2-pyrrolidino-4-hydroxy-6-n-propyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]pyrimidine of the formula C.H. l H 1.

having a melting point of 182-184 C. was prepared from Z-methylmercapto-4-hydroxy-6-n-propyl-5,6,7,8 tetrahydro-pyrido-[4,3-d]-Pyrirnidine and pyrrolidine.

Example 32 Using a procedure analogous to that described in Example 5, 2-piperidino-4-hydroXy-6 n-propyl 5,6,7,8- tetrahydro-pyrido-[4,3-d]pyrimidine of the formula was! (I l.

I OH

having a melting point of 184-185 C. was prepared from 2-methy1mercapto-4-hydroXy-6-n-propyl 5,6,7,8 tetrahydro-pyrido-[4,3-d1-pyrimidine and piperidine.

Example 33 Using a procedure analogous to that described in Example 5, 2-morpho1ino-4-hydroxy-6-n-pr0pyl-5,6,7,8 tetrahydro-pyrido-[4,3-d] -pyrimidine of the formula having a melting point of 186187 C. was prepared from 2-methylmercapto-4-hydroXy-6-n pr-opyl 5,6,7,8 tetrahydro-pyrido-[4,3-d]-pyrimidine and morpholine.

Example 34 Using a procedure analogous to that described in Example 5, 2-(N-methy1-piperazino)-4-hydroxy-6 n propyl- 5,6,8,7-tetrahydro-pyrido-[4,3-d] -pyrimidine of the forhaving a melting point of 148150 C. was prepared from 2-methylmercapto-4-hydroxy-6-n-propyl-5,6,7,8 tetrahydro-pyrido-[4,3-d]pyrimidine and N-methyl-piperazine.

1 1 Example 35 Using a procedure analogous to that described in Example 5, Z-piperidino-4-hydroxy-6-isopropyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 209-2l-1 C. was prepared from Z-rnethylmercapto-4-hydroxy-6-isopropyl-5,6,7,8 tetrahydro-pyriclo-[4,3-d]-pyrimidine and piperidine.

Example 36 Using a procedure analogous to that described in Example 5, 2-morpl1olino-4-hydroXy-6-isopropyl 5,6,7,8 tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I OH having a melting point of 230232 C. was prepared from 2-methylmercapto 4 hydroxy-6-isopropyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine and morphol ine.

Example 37 Using a procedure analogous to that described in Example 5, 2-(di-n-butylamino)-4-hydroXy-6-n-butyl-5,6,7, S-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I OH having a melting point of 104 C. was prepared from 2 methyl-mercapto 4 hydroxy 6 n 5 ,6,7,8-tetrahydropyrido-[4,3-d]-pyrimidine and di-n-butylamine.

Example 38 Using a procedure analogous to that described in Example 5, 2-pyrrolidino-4-hydroxy-6-n-butyl-5,6,7,8 tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 172173 C. was prepared from Z-methylmercapto 4 hydroxy-6-n-butyl-5,6,7,S-tetrahydro-pyrido-[4,3-d1-pyrimidine and pyrrolidine.

Example 39 Using a procedure analogous to that described in EX- ample 5, 2-piperidino-4-hydroxy-6-n-butyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I OH having a melting point of 17l-172 C. was prepared from Z-methylmercapto 4 hydroxy--n-butyl-S,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine and piperidine.

12 Example Using a procedure analogous to that described in Example 5, 2-morpholino-4-hydroXy-6-n-butyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula OH having a melting point of 172 C. was prepared from 2- methylmercapto 4 hydroxy-6-n-butyl 5,6,7,8 tetrahydro-pyrido-[4,3-d]-pyrirnidine and morpholine.

Example 4] Using a procedure analogous to that described in EX- ample 5, 2-(N'-methyl-piperazino)-4-hydroxy-6-n-butyl- 5,6,7,8-tetrahyclro-pyrido-[4,3-d]pyrimidine of the forhaving a melting point of 16l162 C. was prepared from Z-methylmercapto 4 hydroxy-6-n-butyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine and N-methyl-piperazine.

Example 42 Using a procedure analogous to that described in Example 5, Z-n-hexylamino-4-hydroxy-6-isobutyl-5,6,7,8-tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula having a melting point of 146-147" C. was prepared from 2-.rnethylmercapto 4 hydroxy-6-isobutyl-5,6,7,8-tetrahydro-pyrido-[4,3-d1-pyrimidine and n-hexylamine.

Example 43 Using a procedure analogous to that described in Example 5, 2-(di-n-butylamino)-4-l1ydroxy-6-isobutyI-5,6,7, S-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I OH having a melting point of 213 C. was prepared from 2- methyl mercapto 4 hydroxy 6 isobutyl 5,6,7,8- tetrahydro pyrido [4,3 d] pyrimidine and pyrrolidine.

13 Example 45 Using a procedure analogous to that described in Example 5, 2 piperidino 4 hydroxy 6 isobutyl 5,6,7,

8 tetrahydro pyrido [4,3 d] pyrimidine of the formula I lSO--C4H9--N N having a melting point of 197 C. was prepared from 2- methyl mercapto 4 hydroxy 6 isobutyl 5,6,7,8- tetrahydro pyrido [4,3 d] pyrimidine and piperidine.

Example 46 Using a procedure analogous to that described in EX- arnple 5, 2 morpholino 4 hydroxy 6 isobutyl 5,6, 7,8 tetrahydro-pyrido [4,3 d] pyrimidine of the formula having a melting point of 196 C. was prepared from 2- methyl mercapto 4 hydroxy 6 isobutyl 5,6,7,8- tetrahydro pyrido [4,3 d] pyrimidine and morpholine.

Example 47 Using a procedure analogous to that described in Example 5, 2 (N' methyl piperazino) 4 hydroxy- 6 isobutyl 5,6,7,8 tetrahydro pyrido [4,3 d]- pyrimidine of the formula iso- C JED-W l O H having a melting point of 178180 C. was prepared from 2 methylmercapto 4 hydroxy 6 -isbutyl 5,6,7,8- tetrahydro pyrido [4,3 d] pyrimidine and N methyl-piperazine.

Example 48. Preparation of 2-dimetlzylamin0-4-hydroxy 6 -methyl-5,6,7,8-tetmhydr0 pyrido [4, 3-d]-pyrimidine having a melting point of 204-205 C.

14 Example 49 Using a procedure analogous to that described in EX- ample 48, 2 dimethylamino 4 hydroxy 6 allyl 5, 6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 195-196 C. was prepared from N,N-dimethyl-guanidine sulfate and 1-allyl-3-carbethoxy-piperidone-(4) hydrochloride.

Example 50 Using a procedure analogous to that described in Example 5, 2-morpholino-4-hydroxy-6-allyl 5,6,7,8 'tetrahydro-pyrido-[4,3-d]-pyrirnidine of the formula I OH having a melting point of 196197 C. was prepared from Z-methylmercapto-4-hydroxy-6-allyl-5,6,7,8 tetrahydropyrido-[4,3-d1-pyrimidine and morpholine.

Example 51 Using a procedure analogous to that described in Example 5, 2 piperidino 4 hydroXy-6-methyl 7 (or -5) -phenyl-5,6,7,8-tetrahydro-pyrido-[4,3-d] pyrimidine of the formula having a melting point of 240242 C. was prepared from 2-methylmercapto-4-hydroxy-6-methyl-7 (or -5 -phenyl- 5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine and piperidine. (The exact structure has not yet been established.)

Example 52 Using a procedure analogous to that described in EX- ample 4, 2-(di-n-butyl-amin0)-4-hydroXy-6-n-propyl-5,6, 7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 97 C. was prepared from 2-methylmercapto-4-hydroxy-6-n-propyl 5,6,7,8 tetrahydropyrido-[4,3-d1-py1imidine and di-n-butylamine.

Example 53 Using a procedure analogous to that described in EX- ample 5, 2-(benzyl-methyl-amino)-4-hydr0xy-6-n-propyl- 5,6,7,8-tetrahydro-pyrido-[4,3-d] pyrimidine of the forhaving a melting point of 136138 C. was prepared from 2-methylmercapto-4-hydroxy-6-n-propyl 5,6,7,8 tetrahydropyrido-[4,3-d]-pyrimidine and benzyl-methylarnine.

Example 54 Using a procedure analogous to that described in Example 5, Z-(di-n-butylamino)-4-hydroxy-6-isopropyl-5,6, 7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 112 C. was prepared from 2- methylmercapto-4-hydroxy-6 isopro-pyl 5,6,7,8 tetrahydropyrido-[4,3-d]-pyrimidine and di-n-butylamine.

Example 55 Using a procedure analogous to that described in EX- ample 48, 2-dimethylarnino-4-hydroxy-6-n-butyl-5,6,7,8- tetrahydro-pyrido-[4,3-d1-pyrirnidine of the formula having a melting point of 154-156 C. was prepared from N,N-dimethyl-guanidine sulfate and 1-n-butyl-3-carbethoxypiperidone-(4) hydrochloride.

Example 56 Using a procedure analogous to that described in Example 48, 2-dimethylamino-4-hydroxy-6-isobutyl-5,6,7,8- tetrahydro-pyrido-[4,3-d]pyrimidine of the formula I OH having a melting point of 211-212" C. was prepared from N,N-dimethyl-guanidine sulfate and 1-isobutyl-3-carbethoxypiperidone-(4) hydrochloride.

Example 57 Using a procedure analogous to that described in Example 5, 2-n-hexylamino-4-hydroxy-6-n hexyl 5,6,7,8- tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I OH having a melting point of 120-121 C. was prepared from Z-methylrnercapto-4-hydroxy-6-n-hexyl 5,6,7,8 tetrahydropyrido-[4,3-d]-pyrimidine and n-hexylamine.

1 6 Example 58 Using a procedure analogous to that described in Example 5, 2-(2'-ethyl-n-hexyl-arnino) -4-hydroxy-6-n-hexyl- 5,6,7,8-tetrahydro-pyrido-[4,3-d] pyrimidine hydrate of the formula having a melting point of -93 C. was prepared from Z-methylmercapto-4-hydroxy-6-n hexyl 5,6,7,8 tetrahydro-pyrido-[4,3-d]-pyrimidine and ethyl-n-hexylamine.

Example 59 Using a procedure analogous to that described in EX- ample 4, 2-dimethylamino-4-hydroxy-6-n-hexyl 5,6,7,8- tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 8384 C. was prepared from 2- methylmercapto-4-hydroxy-6-n hexyl 5,6,7,8 tetrahydro-pyrido-[4,3-d]-pyrimidine and di-n-butylamine.

Example 61 Using a procedure analogous to that described in Example 5, Z-piperidino-4-hydroxy-6-n-hexyl-5,6,7,8-tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula having a melting point of -161 C. was prepared from Z-methylmercapto-4-hydroxy-6-n-hexyl 5,6,7,8 tetrahydro-pyrido-[4,3-d]pyrimidine and piperidine.

Example 62 Using a procedure analogous to that described in EX- ample 5, 2-morpholino-4-hydroxy-6-n-hexyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]pyrimidine of the formula having a melting point of 157158 C. was prepared from 2-methylmercapto-4-hydroxy-6-n hexyl 5',6,7,8, tetrahydro-pyrido-[4,3-d1-pyrimidine and morpholine.-

1 7 Example 63 Using a procedure analogous to that described in Example 5, Z-n-hexylamino-4-hydroXy-6-n-heXy1-8-methyl- 5,6,7,S-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 64-65 C. was prepared from 2-methylmercapto-4-hydroXy-6-n-hexyl-S-methyl 5,6,7,8- tetrahydro-pyrido-[4,3-d]-pyrimidine and n-hexylamine.

Example 64 Using a procedure analogous to that described in EX- ample 5, Z-(di-n-propylamino)-4-hydroxy-6-n-hexyl-8- methy1-5,6,7,8-tetrahydro-pyrido [4,3-d] pyrimidine of the formula having a melting point of 79-80 C. Was prepared from 2-methylmercapto-4-hydroxy-6-n-hexyl-S-methyl 5,6,7,8- tetrahydro-pyrido [4,3-d] pyrimidine and di-n-propylamine.

Example 65 Using a procedure analogous to that described in Example 5, 2-(di-n-butylarnino)-4 hydroxy 6 n-hexyl-8- methyl-5,6,7,8-tetrahydro-pyrid [4,3-d] pyrimidine of the formula having a melting point of 93-95 C. was prepared from 2-methylmercapto-4-hydroxy-6-n-hexyl-8-methyl 5,6,7,8- tetrahydro-pyrido [4,3-d] pyrimidine and di n-butylamine.

Example 66 Using a procedure analogous to that described in Example 5, 2-piperidino-4-hydroxy-6-n-hexy1-8-methyl-5,6, 7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula All having a melting point of 102-103 C. was prepared from 2-methylmercapto-4-hydroxy-6-n-hexyl-8 methyl 5,6,7, 8-tetrahydro-pyrido'[4,3-d]-pyrimidine and piperidine.

Example 67 Using a procedure analogous to that described in Example 5, 2-(di-n-butylamino)-4 hydroxy 6 isobutyl-S- is methyl-5,6,7,8-tetrahydro-pyriclo [4,3-d] pyrimidine of the formula having a melting point of -121 C. was prepared from Z-methylmercapto-4-hydroxy-6-isobutyl-8 methyl 5,6, 7,S-tetrahydro-pyrido-[4,3-d]-pyrimidine and di-n-butylamine.

Example 68 a-amino-a-imino-pentane sulfate and- 1-methyl-3-carbethoxy-piperidone- (4) hydrochloride.

Example 69 Using a procedure analogous to that described in Example 48, 2-n-propyl-4-hydroxy-6-methy1-8-methyl-5,6, 7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula l' fmaca,

OH:N N

having a melting point of 132-134" C. was prepared from a-amino-a-imino-butane sulfate and 1,5-dimethyl-3-carbethoxy-piperidone-(4)-hydrochloride.

Example 70 Using a procedure analogous to that described in Example 48, 2-n-butyl-4-hydroxy-6-methyl-8-methyl-5,6,7,8-. tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula having a melting point of 131133 C. was prepared from a-amino-a-imino-pentane sulfate and 1,5-dimethyl-3-carbethoxy-piperidone- (4 -hydro-chloride.

Example 71 Using a procedure analogous to that described in Example 3, 2-methyl-4-hydroxy-6-allyl-5,6,7,8-tetrahydropyrido-[4,3-d]-pyrimidine of the formula N \CH: CH1=oH-oH,-N L/N having a melting point of 188189 C.'Was prepared from 1-methyl-3-carbomethoxy-piperidone (4) hydrochloride and acetamidine sulfate.

19 Example 72 Using a procedure analogous to that described in Example 48, 2-n-propyl-4-hydroxy-6-allyl-5,6,7,8-tetrahydropyrido-{4,3-d1-pyrimidine of the formula having a melting point of ll9l20 C. was prepared from 1-allyl-3-carbethoxy-piperidone-(4) hydrochloride and onamino-a-imino-butane sulfate.

Example 73 Using a procedure analogous to that described in EX- ample 48, 2-n-butyl-4-hydroxy-6-allyl-5,6,7,S-tetrahydropyrido-[4,3-d]-pyrimidine of theformula having a melting point of 100-102 C. was prepared from 1-allyl-3-carbethoxy-piperidone-(4) hydrochloride and aamino-a-imino-pentane sulfate.

Example 74 Using a procedure analogous to that described in Example 48, 2,6-di-n-propyl-4-hydroxy-5,6,7,8-tetrahydropyrido-[4,3-d]-pyrimidine of the formula i-4142111, 11- C lHT-N N having a melting point of l-101 C. was prepared from l-n-propyl-3 carbethoxy-piperidone (4) hydrochloride and a-amino-a-imino-butane sulfate.

Example 75 Using a procedure analogous to that described in Example 48, 2-methyl-4-hydroxy-6-isopropyl-5,6,7,B-tetrahaving a melting point of 168-170 C. was prepared from l-isopropyl-B-carbethoxy piperidone (4) hydrochloride and acetamidine sulfate.

Example 76 Using a procedure analogous to that described in Example 48, I 2-n-propyl-4-hydroxy-6'isopropyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I OH having a melting point of 128129 C. was prepared from l-isopropyl-3-carbethoxy-piperidone (4) hydrochloride and a-amino-a-imino-butane sulfate.

25) Example 77 Using a procedure analogous to that described in Example 48, 2-n-butyl-4-hydroxy-6-isopropyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I OH having a melting point of 102-404 C. was prepared from 1-isopropyl-3-carbethoxy-piperidone (4) hydrochloride and a-arnino-a-imino-pentane sulfate.

Example 78 Using a procedure analogous to that described in Example 1, 2-benzyl-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 195-196" C. was prepared from l,6-dimethyl-3-carbomethoxy-piperidone-(4) hydrochloride and phenylacetamidine hydrochloride.

Example 79 Using a procedure analogous to that described in Example 48, 2-n-propyl-4-hydroxy-6-n-buty1-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 103105 C. was prepared from l-n-butyl-3-carbethoxy-piperidone-(4) hydrochloride and a-amino-a-imino-butane sulfatev Example 80 Using a procedure analogous to that described in Example 48, 2-isopropyl-4-hydroxy-6-n-butyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of l79180 C. was prepared from 1-n-butyl-3-carbeth0Xy-piperidone-(4) hydrochloride and isopropyl-formamidine sulfate.

Example 81 Using a procedure analogous to that described in Example 48, 2,6-di-n-butyl-4-hydroxy-5,6,7,8-tetrahydropyrido-[4,3-dJ-pyrimidine of the formula I OH having a melting point of C. was prepared from l-nbutyl-3-carbethoxy-piperid0ne-(4) hydrochloride and aamino-a-imino-pentane sulfate.

2.1 Example 82 Using a procedure analogous to that described in Example 48, 2-methyl-4-hydroxy-6-isobutyl-5,6,7,8-tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula having a melting point of 179-181 C. was prepared from 1-methyl-B-carbethoxy-piperidone-(4) hydrochloride and acetamidine sulfate.

Example 83 Using a procedure analogous to that described in EX- ample 48, 2-n-propyl-4-hydroxy-6-isobutyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 117-118 C. was prepared from l-isobutyl-3-carbethoxy-piperidone-(4) hydrochloride and a-amino-a-irnino-butane sulfate.

Example 84 Using a procedure analogous to that described in Example 48, 2-n-butyl-4-hydroxy-6-isobutyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 113114 C. was prepared from 1-isobutyl-3-carbethoxy-pipe1idone-(4) hydrochloride and a-amino-a-imino-pentane sulfate.

Example 85 Using a procedure analogous to that described in Example 48, 2-benzyl-4-hydroxy-6-isobutyl-5,6,7,S-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula I OH having a melting point of 152-155 C. was prepared from 1-isobutyl-3-carbethoxy-piperidone-(4) hydrochloride and phenylacetamidine sulfate.

Example 86 Using a procedure analogous to that described in Example 1, 2-benzyl-4-hydroxy-6-n-hexyl-5,6,7,S-tetra-hydropyrido-[4,3-d1-pyrimidine of the formula Il-CuHrr-N having a melting point of 120l2l C. was prepared from l-n-hexyl-3-carbomethoxy-piperidone-(4) hydrochloride and phenylacetamidine hydrochloride.

Example 87 Using a procedure analogous to that described in Example 48, 2,8-dimethyl-4-hydroxy-6-n-hexyl-8-methyl- 5,6,7,8-tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula having a melting point of 9597 C. was prepared from l-n-hexyl 3 carbethoxy-S-methyl-piperidone-(4) hydrochloride and acetamidine sulfate.

Example 88 Using a procedure analogous to that described in Example 48, 2-n-butyl-4-hydroxy 6 n hexyl-S-methyl- 5,6,7,S-tetrahydro-pyrido-[4,341]pyrimidine of the formula (I? H: WNWPQ having a melting point of 8889 C. was prepared from l-n-hexyl 3 carbethoxy 5 methyl-piperidone-(4) hydrochloride and phenylacetamidine hydrochloride.

Example 90 Using a procedure analogous to that described in Example 3, 2-(p-chlorobenzyl-mercapto)-4-hydroxy-6,8-dimethyl-5,6,7,8 tetrahydro pyrido-[4,3-d]-pyrirnidine of the formula having a melting point of l88-189 C. was prepared from l,5-dimethyl-3-carbomethoxy-piperidone-(4) hydrochloride and S-(p-chlorobenzyl)-isothiourea sulfate.

Example 91 Using a procedure analogous to that described in Ex ample 3,' 2-(o-chlorobenzyl-mercapto)-4-hydroxy-6,8-dimethyl-5,6,7,8 tetrahydro pyrido-[4,3-d]-pyrirnidine of the formula $H: Cl

N 0 43 Ki/ l O H having a melting point of 197-199 C. was prepared from 1,5-dimethyl 3 carbomethoxy piperidone-(4) hydrochloride and S-(o-chlorobenzyl)-isothiourea sulfate.

23 Example 92 Using a procedure analogous to that described in Example 3, Z-methylmercapto 4 hydroXy-6-allyl-5,6,7,8- tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of l9l-l92 C. was prepared from l-allyl 3 carbomethoxy-piperidone-(4)-hydrochloride and S-methyl-isothiourea sulfate.

Example 93 Using a procedure analogous to that described in Example 3, Z-methylrnercapto 4 hydroxy-6-methyl-7-(or 5)-phenyl-5,6,7,8-tetrahydro pyrido [4,3-d]-pyrimidine of the formula having a melting point of 216218 C. was prepared from 1-methyl-6-(or-2 -pheny1-5,6,7,8-tetrahydro-pyridofrom l-methyl-6-(or-2)-phenyl 3 carbethoxy-piperidone-(4) hydrochloride and S-methyl-isothiourea sulfate. (The exact structure has not yet been established.)

Example 94 Using a procedure analogous to that described in Example 3, 2-methylmercapto-4-hydroxy 6 isobutyl-8- methyl-5,6,7,S-tetrahydro-pyrido [4,3-d] pyrimidine of the formula tso-C dis- W having a melting point of l95-l96 C. was prepared from l-isobutyl-5-methyl-3-carbornethoXy-piperidone (4) hydrochloride and S-methyl-isothiourea sulfate.

Example 95 Using a procedure analogous to that described in EX- ample 3, Z-methylmercapto-4-hydroxy-6-n-hexyl-5,6,7,8- tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula W-SCH:

having a melting point of 168 C. was prepared from 1- n hexyl 3-carbomethoxy-piperidone- (4) hydrochloride and S-methyl-isothiourea sulfate.

Example 96 Using a procedure analogous to that described in Example 3, 2 (p chlorobenzyl-mercapto)-4-hydroXy-6-nhexyl-S,6,7,8-tetrahydro pyrido-[4,3-d]-pyrimidine of the having a melting point of 142-143 C. was prepared from 1 n hexyl-5-methyl-3-carbomethoxy-piperidone- (4) hydrochloride and S-methyl-isothiourea sulfate.

Example 98 Using a procedure analogous to that described in EX- I ample 48, 4-hydroXy-6-methyl-5,6,7,8-tetrahydro-pyrido- [4,3-d]-pyrimidine of the formula having a melting point of 190192 C. was prepared from 1-methyl-3-carbethoxy-piperidone-(4) hydrochloride and formamidine sulfate.

Example 99 Using a procedure analogous to that described in Example 48, 2,6 dimethyl 4 hydroxy-S,6,7,8-tetrahydropyrido-[4,3-d]-pyrirnidine of the formula having a melting point of 214-216 C. was prepared from 1-methyl-3-carbethoXy-piperidone-(4) hydrochloride and acetamidine sulfate.

Example 100 Using a procedure analogous to that described in Example 48, 2-ethyl-4-hydroxy-6-methyl-5,6,7,8-tetrahydropyrido-[4,3-d1-pyrimidine of the formula N N F-CnHa CHa- N l N having a melting point of l167 C. was prepared from 1-methyl-3-carbethoxy-piperidone-(4) hydrochloride and a-amino-a-imino-pmpane sulfate.

Example 101 Using a procedure analogous to that described in EX- arnple 48, 2-n-propyl-4-hydroxy-6-methyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of 159160 C. was prepared from 1-methyl-3-carbethoxy-piperidone-(4) hydrochloride and a-amino-a-i-rnino-butane sulfate.

25 Example 102 Using a procedure analogous to that described in Example 48, 2-isopropyl-4-hydroxy-6-methyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula c CHz-N' N I OH having a melting point of 185-186 C. was prepared from l-methyl-3-carbethoxy-piperidone-(4) hydrochloride and ct-HITllIlO-a-iIIllDO-iSOblllflDC sulfate.

Example 103 I OH j-C 2E1:

having a melting point of 16l-163 C. was prepared from l-isopropyl-3-carbethoxy piperidone (4) hydrochloride and u-amino-u-iminopropane sulfate.

Example 105 Using a procedure analogous to that described in Example 48, 2 dimethylamino 4 hydroxy 6-isopropyl- 5,6,7,8 tetrahydro pyrido [4,3-d] pyrimidine of the formula Y 0 HI I T iso-CzHr-WN I on having a melting point of 173-174 C. was prepared from 1-isopropyl-3-carbethoxy-piperidone (4) hydrochloride and N,N-dimethyl-guanidine sulfate.

Example 106 Using a procedure analogous to that described in Example 48, 2 ethyl 4 hydroxy-6-isobutyl-5,6,7,8- tetrahydro-pyrido-[4,3-cl]-pyrimidine of the formula -0.11. iSO-C4H9W I OH having a melting point of 176-l78 C. was prepared from 1-isobutyl-3-carbeth-oxy-piperidone (4) hydrochloride and a-amino-a-imino-propane sulfate.

26 Example 107 Using a procedure analogous to that described in Example 48, 2-methyl-4-hydroxy-6-n-hexyl-5,6,7,8tetrahydro-pyrido-[4,3-d1-pyrimidine of the formula -orr= Ik-CsHw-N N having a melting point of 138-139 C. was prepared from 1-nhexyl-3-carbethoxy-piperidone-(4) hydrochloride and acetarnidine sulfate.

Example 108 Using a procedure analogous to that described in EX- ample 48, Z-ethyl 4 hydroxy-6-n-hexy1-5,6,7,8 tetrahydro-pyrido-[4,3-d]-pyrimidine of the formula having a melting point of l73l74 C. was prepared from 1-n-hexyl-3-carbethoxy-piperidone-(4) hydrochloride and a-amino-wimino-propane sulfate.

The compounds according to the present invention that is, the tetrahydro-pyrido-[4,3-d]-pyrirnidine substitution products embraced by Formula I and their non-toxic acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit antiphlogistic, antipyretic, diuretic, bacteriostatic, sedative and coronary dilating activities.

Non-toxic, pharmacologically acceptable acid addition salts of the compounds defined by Formula I include, but are not restricted to, those formed with hydrochloric acid, hydrobrornic acid, sulfuric acid, nitric acid, acetic acid, propionic acid, bntyric acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, phthalic acid, cinnamic acid, salicylic acid, nicotinic acid, Z-furoic acid, 8-chlorotheophylline and the like.

For pharmacological purposes, the compounds of the present invention are administered in the form of dosage unit com-positions consisting essentially of an inert, physiologically compatible carrier having uniformly distributed therethrough one eifective dosage unit of a compound of the invention. One eifective dosage unit is 20-300 mgm., preferably 50-200 mgrn.

The following examples illustrate various dosage unit compositions containing a compound according to the present invention as the active ingredient. The parts are parts by Weight unless otherwise specified.

The suppositories are compounded from the following ingredients:

Parts 2-isopropyl-4 hydroxy-6-n-butyl 5,6,7,8 tetrahydro-pyrido-[4,3-d1-pyrimidine 100.0 Suppository base (cocoa butter) 1600.0

Total 1700.0

Example 110.-A queous suspension The suspension is compounded from the following ingredients:

Compounding procednre.The distilled Water is heated to 80 C. The p-hydroxy benzoic acid esters are dissolved in the hot Water, and the colloidal silicic acid is stirred into the solution. Thereafter, a mixture of the sugar and the carboxymethyl cellulose is dissolved in the hot aqueous solution, and the resulting solution is cooled to room temperature. The glycerin and the cocoa essence are added, and then the pyrido-pyrimidine compound is stirred in. The entire mixture is then homogenized. cc. of this suspension contain 100 mgm. of the active ingredient.

Example 111.Tablets The tablet composition is compounded from the following ingredients:

Parts Z-dimethylamino-4-hydroxy 6 allyl-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine 200.0 Lactose 200.0 Corn starch 145.0 Colloidal silicic acid 10.0 Polyvinylpyrrolidone 10.0 Talcum 30.0 Magnesium stearate 5.0

Total 600.0

Compounding procedure-The pyrido-pyrimidine compound is admixed with the lactose, the corn starch and the colloidal silicic acid, and the resulting mixture is granulated by moistening it with an aqueous 8% solution of the polyvinylpyrrolidone and passing the moistened mass through a 1.5 mm.mesh screen. The moist granuate is dried and again passed through the screen, and then the talcum and the magnesium stearate are blended in. The finished mixture is pressed into 600 mgm. tablets. Each table contains 200 mgm. of the active ingredient.

Example 112.-Hyp0dermic solution The solution is compounded from the following ingredients:

Parts Z-dimethylamino-4-hydroxy 6 ally1-5,6,7,8-tetrahydro-pyrido-[4,3-d]-pyrimidine 50.0 Tartaric acid 20.0

Double distilled Water, by vol. 2000.0

Compounding pr0cedure.The tartaric acid and then, While heating to 70 C., the pyrido-pyrirnidine compound were dissolved in about four-fifths of the required amount of distilled water. The resulting solution is cooled to 28 room temperature, diluted to the desired volume with the remaining amount of distilled water and filtered until free from suspended particles. The solution is then filled into White 2 cc.-arnpules, which are sterilized for 20 minutes at C. and sealed. Each ampule contains 50 mgm. of the active ingredient.

Obviously, the above dosage unit composition examples are merely illustrative of the various compositions which may be used to administer the compounds of the present invention. Those skilled in the art will readily understand that the particular tetrahydro-pyrido-pyrimidines in the above dosage unit composition examples may be replaced by any of the other compounds embraced by Formula I or their non-toxic, pharmacologically acceptable acid addition salts. Similarly, the amount of active ingredient in the examples may be varied within the dosage unit limits set forth above, depending upon particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these specific embodiments and that other changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

I claim:

1. 2-n-butyl-4-hydroxy-6,8-dirnethyl 5,6,7,8 tetrahydro-pyrido-[4,3-d]-pyrimidine.

2. 2-isopropyl-4-hydroxy-6-n-butyl 5,6,7,8 tetrahydro-pyrido-[4,3-d1-pyrimidine.

3. 2-benzyl-4-hydroxy-6-isobutyl 5,6,7,8 tetrahydropyrido-[4,3-d]-pyrimidine.

4-. 2-henzyl-4-hydroxy-6-n-hexyl 5,6,7,8 tetrahydropyrido-[4-3-d]-pyrimidine.

5. 2-dirnethylamino-4-hydroxy-6-n propyl 5,6,7,8- tetrahydro-pyrido- [4,3 -d -pyrimidine.

6. Z-(di-n-butylamino)-4-hydroXy-6-n-propyl 5,6,7,8- tetrahydro-pyrido- [4,3-d] pyrimidine.

7. 2-dimethylamino-4-hydroXy-6-a1lyl 5,6,7,8 tetrahydro-pyrido- [4,3 -d] -pyrimidine.

8. 2-dirnethylamino-4-hydroxy-6-n-butyl 5,6,7,8-tetrahydro-pyrido- [4,3-d] -pyrimidine.

9. 2-dirnethylamino-4-hydroxy-6-isobutyl 5,6,7,8-tetrahydro-pyrido- [4,3 -d] -pyrimidine.

10. 2-(di-n-butylamino)-4-hydroXy-6-isobutyl 5,6,7,8- tetrahydro-pyrido- [4, 3-d] -pyrimidine.

References Cited by the Examiner UNITED STATES PATENTS 2,697,710 12/1954 Hitchings et al. 260256.4 2,890,152 6/1959 Babcock et al. 16765 2,926,166 2/1960 Hitchings et al. 260256.4 2,994,640 8/1961 Zellner l67-65 3,149,106 9/1964 Loev 260256.4

OTHER REFERENCES Cook et al.: Jour. Chem. Soc. (London), 1945, pages Fieser et al.: Organic Chemistry, D.C. Heath & Co., Boston,'1956, pages 4667.

ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO', HENRY R. JILES, Examiners.

ALTON D. ROLLINS, MARY U. OBRIEN,

Assistant Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,306,901 February 28, 1967 Gerhard Ohnacker It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 48, formula III, the formula should appear as shown below instead of as in the patent:

column 3, line 72, the last formula, the formula should appear as shown below instead of as in the patent:

CH 2 S iI; N

column 7, lines 66 to 71, the formula should appear as shown below instead of as in the patent n-C H N Y column 23 line 31 strike out "from l-methyl-6- (or-2) -phenyl- 5,6,7,8-tetrahydropyrido-"; column 26, line 27, for "173- 174 C read 146-147 C.

Signed and sealed this 7th day of November 1967.

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents EDWARD M.FLETCHER,JR. Attesting Officer 

1. 2-N-BUTYL-4-HYDROXY-6,8-DIMETHYL - 5,6,7,8 - TETRAHYDRO-PYRIDO-(4,3-D)-PYRIMIDINE. 